The invention relates to novel adhesion receptor antagonists of the formula I 
in which
R is 
xe2x80x83with
B=CH2, CO or CS, R10=OH or H and
m=0, 1, 2, 3 or 4; 
xe2x80x83with
B=CH2, CO or CS, U=CH2 or CO,
R9=H, CO2H or CO2A and q=0, 1, 2 or 3; 
xe2x80x83with
n=1, 2, 3 or 4; 
xe2x80x83with
R4=H, Axe2x80x94SO2, Arxe2x80x94SO2, Axe2x80x94CO, Arxe2x80x94CO or
Hetxe2x80x94CO; 
xe2x80x83with
R5=H, A, alkynyl or alkenyl with in each
case 2-5 C atoms, or Ar; 
xe2x80x83with
D, E, F and G each, independently of one another, CH or N and
k and 1 each, independently of one another, 0, 1, 2, 3 or 4, where k=0 is excluded when E and F are each N and 1=0 is excluded when G=N; 
where AA is an amino acid residue selected from a group consisting of residues of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr or Val, which is bonded by peptide linkages; 
xe2x80x83with
R6=H or A and
m in each case independently of one another 0, 1, 2, 3 or 4; 
xe2x80x83with
R7=OH, OA, OAr, OHet, NHOH, NH2, NHA or NA2,
R8=H or A and
n in each case independently of one another 1, 2, 3 or 4; or 
xe2x80x83where R4 has the meaning already indicated under (d), and p is 2, 3, 4, 5 or 6;
R1 is H, A, Arxe2x80x94CO, Axe2x80x94CO, OH, OA or AOxe2x80x94CO;
R2 is OH, OA, OAr, OHet, NHOH, NH2, NHA or NA2;
R3 is Axe2x80x94CO, Arxe2x80x94CO, Hetxe2x80x94CO, Hetxe2x80x94Oxe2x80x94CO, Arxe2x80x94Oxe2x80x94CO, Axe2x80x94Oxe2x80x94CO, Arxe2x80x94SO2 or Axe2x80x94SO2;
A is alkyl with 1 to 6 C atoms;
Ar is aryl of 6 to 10 C atoms, e.g., phenyl, naphthyl, or diphenylmethyl or benzyl, which are unsubstituted or substituted once, twice or three times by A, F, Cl, Br, I, OA, xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94, COOA, COOH, CF3, OH, NO2, CN, Oxe2x80x94COxe2x80x94A, NH2, NHA or NA2, and
Het is a mono- or binuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and/or S atoms, which can be unsubstituted or substituted once by F, Cl, Br, CF3, A, OH, OA, CN or NO2,
and their physiologically acceptable salts and solvates.
Similar compounds are disclosed in EP-A1-0 623 615 (DE 43 14 378).
The invention has an object of finding novel compounds with valuable properties, in particular those which can be used to produce pharmaceuticals.
Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.
This object has been achieved by the invention. It has been found that the compounds of the formula I and their solvates and salts have valuable pharmacological properties while being well tolerated. In particular, they act as integrin inhibitors, and they inhibit, in particular, the interactions of the xcex23 or xcex25 integrin receptors with ligands. The compounds show particular activity in the case of the integrins xcex1vxcex23, xcex1vxcex25 and xcex1IIbxcex23. This effect can be demonstrated, for example, by the method described in J. W. Smith et al. in J. Biol. Chem., 2265, 12267-12271 (1990). In particular, they inhibit the binding of fibrinogen, fibronectin and von-Willebrand factor to the fibrinogen receptor of blood platelets (glycoprotein IIb/IIIa) and the binding thereof and of other adhesive proteins, such as vitronectin, collagen and laminin, to the corresponding receptors on the surface of various types of cells. The compounds thus influence cell-cell and cell-matrix interactions. They prevent, in particular, the development of blood platelet thrombi and can therefore be used for the treatment of thromboses, stroke, myocardial infarct, angina pectoris, osteolytic disorders, especially osteoporosis and restenosis after angioplasty, ischemias, inflammations, arteriosclerosis and acute kidney failure, for example. The compounds inhibit or prevent vessel development and thus also show an antiangiogenetic effect. The compounds furthermore have an effect on tumor cells by inhibiting metastasis thereof. They can thus also be used as antitumor agents.
There is evidence that tumor cells gain access to vessels through microthrombi and thus are protected from detection by the cells of the immune system. Likewise, microthrombi act to assist the binding of tumour cells to vessel walls. Since the formation of microthrombi is connected with the binding of fibrinogen to the fibrinogen receptor (glycoprotein IIb/IIIa), fibrinogen binding inhibitors are regarded as also being metastasis inhibitors. Their antiangiogenetic capabilities mean that they prevent tumor cells from being supplied with blood and nutrients.
The compounds are additionally suitable as antimicrobial agents which are able to prevent infections like those caused, for example, by bacteria, fungi or yeasts. The substances can therefore be preferably given as concomitant antimicrobial agents when interventions are performed on organisms in which exogenous substances such as, for example, biomaterials, implants, catheters or cardiac pacemakers are inserted. They act as antiseptics. Antimicrobial activities of the compounds can be demonstrated, for example, by the method of P. Valentin-Weigand et al., described in Infection and Immunity, 2851-2855 (1988).
The other properties of the compounds can be demonstrated by methods described in EP-A1-0 462 960. Inhibition of the binding of fibrin to the fibrinogen receptor can be demonstrated by the method indicated in EP-A1-0 381 033. The platelet aggregation inhibiting effect can be demonstrated in vitro by the method of Born (Nature 4832, 927-929, (1962)).
The invention furthermore relates to a process for the preparation of a compound of the stated formula I and of its salts, characterized in that
(i) a compound of the formula I is liberated from one of its functional derivatives by treatment with a solvolyzing or hydrogenolyzing agent, or in that
(ii) a compound of the formula II 
xe2x80x83in which
R, R1 and R2 have the stated meanings, is reacted with a compound of the formula III
R3xe2x80x94Xxe2x80x83xe2x80x83III,
xe2x80x83in which
R3 has the stated meaning, and
X is OH, F, Cl, Br, I or another easily displaceable leaving group, or in that
(iii) to prepare a compound of the formula I with R=(a), (b), (c) or (d),
a compound of the formula IV 
xe2x80x83above,
R* is 
xe2x80x83where R1 and R3, as well as B, have the meanings stated above, and
Z is Cl, Br, I, OH or a reactively esterified OH group,
is reacted with a compound of the formula Va 
xe2x80x83in which
Y is xe2x80x94CHxe2x80x94(CH2)mxe2x80x94COR2, xe2x80x94Nxe2x80x94CHR9xe2x80x94(CH2)qxe2x80x94COR2 or xe2x80x94Nxe2x80x94(CH2)nxe2x80x94COR2, where U, R2, R9, m, q and n have the meanings stated above,
or with a compound of the formula Vb 
xe2x80x83in which
L is xe2x80x94(CH2)nxe2x80x94COR2 or xe2x80x94CH2xe2x80x94CH(NHR4)xe2x80x94COR2, where R2, R4 and n have the meanings stated above, and
Xxe2x80x2 is OH or a salt-like radical which can be derived from OH, or in that
a compound of the formula VI 
xe2x80x83in which
T is 
xe2x80x83or 
xe2x80x83where B, L, U and Y, and
R1 and R3 have the meanings already stated, is reacted with a reactive derivative of carbonic acid, or in that
(iv) to prepare a compound of the formula I with R=(e), (f), (g), (h), (i) or (k), a compound of the formula VII 
xe2x80x83in which
R1 and R3 have the meanings already stated, and
M is 
xe2x80x83xe2x80x94NR6H or xe2x80x94CONR8H, where D, E, F, X, Xxe2x80x2, AA, R6, R8 and k have the meanings already stated,
is reacted with a compound of the formula VIII
R2xe2x80x94COxe2x80x94Qxe2x80x83xe2x80x83VIII,
xe2x80x83in which
R2 has the stated meaning, and
Q is
xe2x80x94CH2xe2x80x94CHR5xe2x80x94NHCOxe2x80x94(CH2)2xe2x80x94COX, xe2x80x94CH2xe2x80x94CHR5xe2x80x94NH2, 
where F, G, X, R5, R7, AA, k, l, m and n have the meanings already stated, or in that
(v) to prepare a compound of the formula I with R=(1), a compound of the formula IX 
xe2x80x83in which
R1, R3, X and p have the stated meanings,
is reacted with a compound of the formula X 
xe2x80x83in which
R2, R4 and Xxe2x80x2 have the stated meanings,
or in that to prepare a compound of the formula I, in a compound which corresponds per se to the formula I
(vi) a radical R1 is converted into a different radical R1 by
alkylation or acylation, or in that
(vii) a radial R2 is converted into a different radical R2 by
alkylation of an amide
complete or partial hydrolysis of a cyano group
esterification of a COOH group or
conversion of a COOH or COOA group into an amide, or in that
(viii) a compound of the formula I according to claim 1 is converted by treatment with an acid or base into one of its salts.
The compounds of the formula I have at least one chiral center and may therefore exist in several enantiomeric forms. All these forms (for example R and S forms) and mixtures thereof (for example the RS forms) are included in the formula I.
Hereinbefore and hereinafter, all radicals and parameters have the meanings stated for formulae I to X unless expressly stated otherwise. If a plurality of groups or parameters with the same symbols are present in the molecule, they may, independently of one another, assume different definitions.
The group A in the above formulae has 1-6, preferably 1, 2, 3 or 4, C atoms. Specifically, A is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl.
The radical 
is particularly preferably 
with m=0 or 1 or 
with
U=CO or CH2 and
n=1 or 2
but furthermore also preferably 
with R4=H, Axe2x80x94SO2 or Arxe2x80x94SO2; 
with
q=1 or 2 and
R=COOH, COOA or H; 
with R5=H, A, alkynyl or alkenyl with 2-4 C atoms or Ar; 
with 1=1 or 2; 
with 1=1 or 2; 
with R6=H or A; 
with R4=SO2A or 
where AA is an amino acid residue selected from a group consisting of residues of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr or Val, which is bonded via peptide linkages.
R1 is preferably hydrogen, methyl or ethyl.
R2 is preferably OH or OA, but also preferably phenylxe2x80x94CH2xe2x80x94Oxe2x80x94(benzyloxy), while R3 is preferably Axe2x80x94CO, Arxe2x80x94CO, Hetxe2x80x94CO, Arxe2x80x94Oxe2x80x94CO, Arxe2x80x94SO2 or Axe2x80x94SO2.
Ar is preferably phenyl, benzyl or diphenylmethyl, but furthermore also preferably 1- or 2-naphthyl, where the said radicals are preferably unsubstituted but can also be substituted once, twice or three times by the said radicals, in particular A, F, Cl, Br, methylenedioxy, COOH, COOCH3, Oxe2x80x94COxe2x80x94A, COOC2H5, CF3, OH or OA.
Het is preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothioazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, and further preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzthiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl. The heterocyclic radicals can also be partially or completely hydrogenated.
Het can thus also be, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1,2,3,6-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazanyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or 8-isoquinolinyl.
It applies to the invention in its entirety that all radicals which occur more than once can be identical or different, that is to say are independent of one another.
Accordingly, the invention particularly relates to those compounds of the formula I in which at least one of the said radicals has one of the meanings stated above as preferred. Some preferred groups of compounds can be expressed by the following formulae Ia to Ih, which correspond to the formula I and in which the undefined radicals have the meaning stated for formula I, but in which
in Ia R is 
xe2x80x83and n is 1 or 2 and R1 is hydrogen;
in Ib R is 
xe2x80x83R10 is hydrogen or OH, m is 0 or 1 and R1 is hydrogen;
in Ic R is 
xe2x80x83and R1 is hydrogen;
in Id R is 
xe2x80x83with 1=1 or 2, and R1 is hydrogen;
in Ie R is 
xe2x80x83R1 is hydrogen and R2 is OH or OA;
in If R is 
xe2x80x83with R5=A, alkenyl or alkynyl with 2-4 C atoms; 
or 
or 
with
R4=Axe2x80x94SO2xe2x80x94 or Arxe2x80x94SO2xe2x80x94;
in Ig R3 is benzoyl, 1- or 2-naphthoyl, furoyl, thienoyl or carbobenzoxy and R2 is OH or OA;
in Ih R is 
xe2x80x83n is 1 or 2, U is CO or CH2, R2 is OH or OA and R3 is benzoyl or 1- or 2-naphthoyl.
The compounds of the formula I as well as the starting materials for preparing them are moreover prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of organic chemistry], Georg-Thieme-Verlag, Stuttgart; also J. Med. Chem. 37, 3881-3886 (1994), EP-A1-0 381 033, EP-A1-0 462 960), specifically under reaction conditions known and suitable for the said reactions. It is moreover also possible to make use of variants which are known per se but not mentioned here in detail.
The starting materials can, if required, also be formed in situ, so that they are not isolated from the reaction mixture but immediately reacted further to give the compounds of the formula I.
The compounds of the formula I can be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis.
Preferred starting materials for the solvolysis or hydrogenolysis are those which otherwise correspond to the formula I but contain, in place of one or more free amino and/or hydroxyl groups, corresponding protected amino and/or hydroxyl groups, preferably those which have in place of an H atom which is bonded to an N atom an amino protective group, in particular those which have in place of an HN group an Rxe2x80x2xe2x80x94N group in which Rxe2x80x2 is an amino protective group, and/or those which have in place of the H atom of a hydroxyl group a hydroxyl protective group, for example those which correspond to the formula I but have in place of a xe2x80x94COOH group a xe2x80x94COORxe2x80x3 group in which Rxe2x80x3 is a hydroxyl protective group.
It is also possible for a plurality of identical or different protected amino and/or hydroxyl groups to be present in the molecule of the starting material. If the protective groups which are present differ from one another, they can in many cases be eliminated selectively.
The term xe2x80x9camino protective groupxe2x80x9d is generally known and refers to groups which are suitable for protecting (blocking) an amino group from chemical reactions but which can easily be removed after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl (for example 2,4-dinitrophenyl (DNP)), aralkoxymethyl (for example benzyloxymethyl (BOM)) or aralkyl groups (for example benzyl, 4-nitrobenzyl, triphenylmethyl). Since the amino protective groups are removed after the desired reaction (or sequence of reactions), their nature and size is moreover not critical; however, those with 1-20, in particular 1-8, C atoms are preferred. The term xe2x80x9cacyl groupxe2x80x9d in connection with the present process is to be interpreted in the widest sense. It embraces acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxycarbonyl, aryloxycarbonyl and, especially, aralkoxycarbonyl groups. Examples of acyl groups of these types are alkanoyls such as acetyl, propionyl, butyryl; aralkanoyls such as phenylacetyl; aroyls such as benzoyl or toluyl; aryloxyalkanoyls such as phenoxyacetyl; alkoxycarbonyls such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl (BOC), 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as benzyloxycarbonyl (CBZ), 4-methoxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC). Preferred amino protective groups are BOC, DNP and BOM, also CBZ, benzyl and acetyl.
The term xe2x80x9chydroxyl protective groupxe2x80x9d is likewise generally known and refers to groups which are suitable for protecting a hydroxyl group from chemical reactions but which can easily be removed after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups. The nature and size of the hydroxyl protective groups is not critical because they are removed again after the desired chemical reaction or sequence of reactions; preferred groups have 1-20, in particular 1-10, C atoms. Examples of hydroxyl protective groups are, inter alia, tert-butyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl and acetyl, with benzyl and acetyl being particularly preferred.
The functional derivatives of the compounds of the formula I which are to be used as starting materials can be prepared by conventional methods as described, for example, in the stated standard works and patents, for example by reacting compounds which correspond to the formula II and III but where at least one of these compounds contains a protective group in place of an H atom.
The liberation of the compounds of the formula I from their functional derivatives takes place, depending on the protective group used, for example with strong acids, preferably with trifluoroacetic acid. or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene- or p-toluenesulfonic acid. The presence of an additional inert solvent is possible but not always necessary.
Suitable and preferred inert solvents are organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide (DMF), halogenated hydrocarbons such as dichloromethane, sulfoxides such as dimethyl sulfoxide (DMSO), furthermore also alcohols such as methanol, ethanol or isopropanol, and water. Mixtures of the abovementioned solvents are also suitable.
Trifluoroacetic acid is preferably used in excess without addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1. The reaction temperatures for the cleavage are preferably from about 0 to about 50xc2x0 C., preferably from 15 to 30xc2x0 C. (room temperature).
The BOC group can be eliminated, for example, preferably with 40 trifluoroacetic acid in dichloromethane or with about 3 to 5 N HCl in dioxane at 15-60xc2x0 C., and the FMOC group with an approximately 5-20% solution of dimethylamine, diethylamine or piperidine in DMF at 15-50xc2x0. The DNP group is eliminated, for example, also with an approximately 3-10% solution of 2-mercaptoethanol in DMF/water at 15-30xc2x0.
Protective groups which can be eliminated by hydrogenolysis (for example BOM, CBZ or benzyl) can be eliminated, for example, by treatment with hydrogen in the presence of a catalyst (for example of a noble metal catalyst such as palladium, preferably on a support such as carbon). Suitable solvents in this case are those mentioned above, especially, for example, alcohols such as methanol or ethanol or amides such as DMF. The hydrogenolysis is, for example, carried out at temperatures from about 0 to 100xc2x0 C. and at pressures from about 1 to 200 bar, preferably 20-3.0xc2x0 C. and 1-10 bar. Hydrogenolysis of the CBZ group takes place satisfactorily, for example, on 5-10% Pdxe2x80x94C in methanol at 20-30xc2x0 C.
Compounds of the formula I can preferably also be obtained by reacting a compound of the formula II with a carboxylic acid derivative of the formula III. In this case the known methods for the acylation of amines are preferably used.
The group X in the formula III is preferably Cl, Br, I, C1-C6-alkylsulfonyloxy such as methane- or ethanesulfonyloxy or C6C10-arylsulfonyloxy such as benzene-, p-toluene- or 1- or 2-naphthalenesulfonyloxy.
The reaction preferably takes place in the presence of an additional base, for example of an alkali metal or alkaline earth metal hydroxide or carbonate such as sodium, potassium or calcium hydroxide, sodium, potassium or calcium carbonate, in an inert solvent, for example a halogenated hydrocarbon such as dichloromethane, an ether such as THF or dioxane, an amide such as DMF or dimethylacetamide, a nitrile such as acetonitrile, at temperatures from about xe2x88x9210 to 200xc2x0 C., preferably from 0 to 120xc2x0 C. If the leaving group is different from iodine, it is advisable to add an iodide such as potassium iodide.
The starting materials of the formula II are, generally, known and can be prepared, for example, by the methods described in EP 0 623 615 (corresponding to DE 43 14 378).
To prepare an amidine of the formula II, ammonia can be added onto a nitrile of the formula II. The addition preferably takes place in several stages by, in a manner known per se, a) converting the nitrile with H2S into a thioamide which is converted with an alkylating agent, for example CH3I, into the corresponding S-alkylimidothioester which in turn reacts with NH3 to give the amidine, b) converting the nitrile with an alcohol, for example ethanol, in the presence of HCl into the corresponding imidoester and treating the latter with ammonia, or c) reacting the nitrile with lithium bis(trimethylsilyl)amide and subsequently hydrolyzing the product.
The corresponding N-hydroxyamidines of the formula II can be obtained analogously from the nitrites when hydroxylamine is used in place of ammonia in a) or b). These products can then also be modified by, for example, reducing them with hydrogen gas.
The compounds of the formula III are known and most of them are commercially available.
Reaction of compounds II with compounds III takes place as already described previously.
It is furthermore possible to obtain a compound of the formula I in which R is (a), (b), (c) or (d) by reacting a compound of the formula IV with a compound of the formula Va or Vb.
Some of the compounds of the formula IV are disclosed in EP 0 623 615, or they can be prepared by the methods described therein.
They can be prepared, for example, by reacting a substituted aniline of the formula R*xe2x80x94NH2 with a compound of the formula R5CH2xe2x80x94CHR6xe2x80x94CH2OH (in which R5 is Cl, Br or another suitable leaving group, and R6 is OH or R5 and R6 together are also O) to give a compound of the formula R*xe2x80x94NHxe2x80x94CH2xe2x80x94CHR8xe2x80x94CH2OH (in which R8 is OH), reacting with a derivative of carbonic acid such as diethyl carbonate to give 3-R*-5-hydroxymethyl-2-oxazolidinones and, where- appropriate, converting the hydroxymethyl group into a CH2Zxe2x80x2 group (where Z is a leaving group), for example with SOCl2, SOBr2, methanesulfonyl chloride or p-toluenesulfonyl chloride. The compounds of the formula Vb are, generally, known or can be prepared in analogy to known compounds from suitable phenol derivatives or from phenol. The same applies to compounds of the formula Va. They can be prepared by methods known per se from piperidine or piperazine derivatives.
The reaction takes place under similar conditions as previously described for the reaction between compounds II and III.
Compounds of the formula I can furthermore be obtained by reacting a compound of the formula IV (or a reactive derivative thereof) with a reactive derivative of carbonic acid.
Particularly suitable carbonic acid derivatives are dialkyl carbonates such as diethyl carbonate, furthermore also alkyl chloroformates such as ethyl chloroformate. The carbonic acid derivative is preferably used in excess and preferably also serves as solvent or suspending agent.
However, it is also possible for one of the stated solvents to be present as long as it is inert in this reaction. It is furthermore advisable to add a base, in particular an alkali metal alcoholate such as potassium tert-butoxide. The reaction is preferably carried out at temperatures from 0 to 150xc2x0 C., preferably from 70 to 120xc2x0 C.
The starting materials of the formula IV are, as a rule, novel. They can be obtained, for example, by functionalization of the abovementioned compounds of the formula R*xe2x80x94NHxe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CH2OH to give compounds of the formula R*xe2x80x94NHxe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94Z and reaction with compounds of the formula Va or Vb.
It is likewise possible to obtain compounds of the formula I in which 
is (e), (f), (g), (h), (i) or (k) by reacting a compound of the formula VII with a compound of the formula VIII.
The preparation of compounds VII and VIII can take place by methods known per se as described, for example, in J. March, Adv. Org. Chem. 3rd Edition, J. Wiley and Sons (1985).
Thus, for example, it is possible to prepare a compound of the formula VII by converting a p-CN-aniline which is, where appropriate, derivatized on the NH2 group, as previously described, into a p-amidinoaniline and subsequently to acylate the latter with a compound of the formula R3xe2x80x94X where X is preferably Cl or Br. It is furthermore possible for a benzoic acid derivative which is substituted by the radical R3xe2x80x94NHxe2x80x94C(xe2x95x90NR1) to be converted into another acid derivative or be linked to an amino acid or an appropriately derivatized amino acid in order to obtain a compound of the formula VII.
The preparation of the carboxylic acids or carboxylic acid derivatives of the formula VIII is trivial and can take place by methods known per se.
The reaction of VII with VIII is likewise preferably carried out in the presence of a base or with an excess of the basic component. Suitable and preferred bases are, for example, alkali metal or alkaline earth metal hydroxides, carbonates, alcoholates or organic bases such as triethylamine or pyridine, which can also be used in excess and then may simultaneously serve as solvents.
Particularly suitable inert solvents are alcohols such as methanol, ethanol, or isopropanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, THF or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; nitriles such as acetonitrile; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate; amides such as hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide (DMSO); chlorinated hydrocarbons such as dichloromethane, chloroform, trichloroethylene, 1,2-dichloroethane or carbon tetrachloride; hydrocarbons such as benzene, toluene or xylene. Mixtures of these solvents with one another are also suitable.
Preferred reaction temperatures are between room temperature and the boiling point of the solvent chosen.
Compounds of the formula I can also be prepared by reacting a compound of the formula IX with a compound of the formula X.
Concerning the preparation of the precursors IX and X, and the reaction of the two compounds with one another, what has already been said above for the compounds VII and VIII applies.
It is furthermore possible to convert a radical R2 in a compound of the formula I into another radical R2 by hydrolyzing an ester of the formula I or esterifying a carboxylic acid of the formula I.
For esterification, an acid of the formula I (R2xe2x95x90H) can be treated with an excess of an alcohol of the formula R2xe2x80x94OH (R2xe2x95x90A or benzyl), preferably in the presence of a strong acid such as hydrochloric acid or sulfuric acid at temperatures from 0 to 100xc2x0 C., preferably 20 to 50xc2x0 C.
Conversely, an ester of the formula I (R2xe2x95x90A or benzyl) can be converted into the corresponding acid of the formula I (R2xe2x95x90H), preferably by solvolysis or hydrogenolysis by one of the methods stated above, for example with NaOH or KOH in water/dioxane at temperatures from 0 to 40xc2x0 C., preferably 10 to 30xc2x0 C.
It is likewise possible for cyano groups to be completely or partially hydrolyzed.
It is furthermore possible to convert one radical R1 and/or R3 into another radical R1 and/or R3.
In particular, primary or secondary amino groups can be alkylated, acylated, amidinated or provided with conventional amino protective groups or alkyl- or arylsulfonyl groups or, conversely, be liberated by removing these groups.
A base of the formula I can be converted with an acid into the relevant acid addition salt. Particularly suitable acids for this reaction are those which afford physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, trifluoroacetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and -disulphonic acids, lauryl sulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used to isolate and/or purify the compounds of the formula I.
The free bases of the formula I can, if required, be liberated from their salts by treatment with strong bases such as sodium or potassium hydroxide, sodium or potassium carbonate.
It is also possible to convert carboxylic acids of the formula I (R2=H) by reaction with appropriate bases into their metal or ammonium salts, for example their sodium, potassium or calcium salts.
The compounds of the formula I contain one or more chiral centers and may therefore exist in racemic or optically active form. Racemates which are obtained can be separated by methods known per se, mechanically or chemically, into the enantiomers. Diastereomers are preferably formed from the racemic mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as xcex2-camphorsulfonic acid. It is also advantageous to separate enantiomers using a column packed with an optically active resolving agent (for example dinitrobenzoyl-phenylglycine); suitable as mobile phase is, for example, a hexane/isopropanol/acetonitrile mixture, for example in the ratio 82:15:3 by volume.
It is, of course, also possible to obtain optically active compounds of the formula I in the methods described above by using starting materials (for example those of the formula II) which are already optically active.
The compounds of the formula I may likewise occur in tautomeric forms. The invention includes all these tautomers.
The novel compounds of the formula I and their physiologically acceptable salts can be used to produce pharmaceutical products by converting them, together with at least one vehicle or ancillary substance and, if required, together with one or more other active substance(s), into a suitable dosage form. The formulations obtained in this way can be used as pharmaceuticals in human or veterinary medicine. Suitable carrier substances are organic or inorganic substances which are suitable for enteral (for example oral or rectal) or parenteral administration or for administration in the form of an inhalation spray and which do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycerides, gelatin, soya lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc, cellulose. Used for oral administration are, in particular, tablets, coated tablets, capsules, syrups, solutions or drops; specifically of interest are lacquered tablets and capsules with coatings or capsule shells which are resistant to gastric fluid. Used for rectal administration are suppositories, and for parenteral administration are solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants.
For administration as inhalation sprays it is possible to use sprays which contain the active substance either dissolved or suspended in a propellant gas mixture. In this case, the active substance is preferably used in micronized form, it being possible for one or more additional physiologically tolerated solvents to be present, for example ethanol. Inhalation solutions can be administered with the aid of conventional inhalers. The novel compounds can also be lyophilized, and the resulting lyophilizates can be used, for example, to produce injectable products. The stated formulations can be sterilized and/or contain ancillary substances such as preservatives, stabilizers and/or wetting agents, emulsifiers, salts to influence the osmotic pressure, buffer substances, colorants and/or flavorings. They can, if required, also contain one or more other active substances, for example one or more vitamins.
The substances according to the invention are, for example, administered in analogy to other known drugs which are commercially available, but especially in analogy to the compounds described in EP-A-459 256, preferably in doses from about 5 mg to 1 g, in particular from 50 to 500 mg, per dosage unit. The daily dosage is preferably from about 0.1 to 20 mg/kg, in particular 1 to 10 mg/kg, of body weight. The specific dose for each particular patient depends, however, on a wide variety of factors, for example on the activity of the specific compound used, on the age, body weight, general state of health, sex, on the diet, on the time and route of administration, on the rate of excretion, medicinal substance combination and severity of the particular disorder for which the therapy is applied. Oral administration is preferred.
Hereinbefore and hereinafter, all temperatures are stated in xc2x0 C. In the following examples, xe2x80x9cusual working upxe2x80x9d means: if required, water is added, the pH is adjusted to between 2 and 8, depending on the nature of the final product, filtration through an ion exchange column is carried out, the organic phase is dried over sodium sulfate, evaporated, lyophilized where appropriate and purified by chromatography on silica gel and/or crystallization. In the following examples, xe2x80x9c4-piperidylethylxe2x80x9d always means xe2x80x9c2-(4-piperidyl)ethyl,xe2x80x9d xe2x80x9c4-piperidylpropylxe2x80x9d always means xe2x80x9c3-(4-piperidyl) propylxe2x80x9d and xe2x80x9c4-piperidylbutylxe2x80x9d always means xe2x80x9c4-(4-piperidyl)butyl.xe2x80x9d Likewise, xe2x80x9c4-piperazinylethylxe2x80x9d always means xe2x80x9c2-(4-piperazinyl) ethyl,xe2x80x9d xe2x80x9c4-piperazinylpropylxe2x80x9d means xe2x80x9c3-(4-piperazinyl)propylxe2x80x9d and xe2x80x9c4-piperazinylbutylxe2x80x9d means xe2x80x9c4-(4-piperazinyl)butyl.xe2x80x9d These also include the derivatives provided with protective groups, for example the BOC-protected compounds.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, unless otherwise indicated, all parts and percentages are by weight.
The entire disclosure of all applications, patents and publications, cited above and below, and of corresponding German application 195 16 483.0, filed May 5, 1995, are hereby incorporated by reference.